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Background: Clinical worsening (CW) is commonly used as an endpoint in pulmonary arterial hypertension (PAH) trials. The use of composite endpoints is based on the assumption that each component is interchangeable.

Objectives: We aimed to assess the trial-level surrogacy of CW for predicting overall mortality (considered adequate when coefficient of determination R²_trial >0.70) in PAH trials. We also assessed whether the various CW components were similar in terms of: 1) frequency of occurrence; 2) treatment-related relative risk (RR) reduction and; 3) importance to patients.

Methods: We searched MEDLINE, Embase, and the Cochrane Library (01/1990-12/2020) for RCTs evaluating the effects of PAH treatment on CW. The R²_trial between the RR for CW and mortality (including after censoring) was analysed by regression analysis. The frequency of occurrence of the CW components, as well as the RR …